JP2019534299A - Process for producing (S) -N1- (2-aminoethyl) -3- (4-alkoxyphenyl) propane-1,2-diamine trihydrochloride - Google Patents

Abstract

The present invention relates to a novel process for preparing (S) -N1- (2-aminoethyl) -3- (4-alkoxyphenyl) propane-1,2-diamine trihydrochloride.

Description

The present invention relates to a novel process for preparing (S) —N ^1- (2-aminoethyl) -3- (4-alkoxyphenyl) propane-1,2-diamine trihydrochloride.

EOVIST (registered trademark) is a paramagnetic contrast agent for magnetic resonance imaging (MRI) and is used for MRI of blood vessels, tissues, and other non-osseous tissues, and is particularly useful for diagnosing abnormalities in liver tissues. is there. EOVIST® contains gadoxetate disodium as a pharmaceutically active ingredient, has a molecular weight of 725.72, a chemical formula of GdC ₂₃ H ₂₈ N ₃ O ₁₁ Na ₂ , and gadolinium (4S) -4- ( It has the structural formula of 4-ethoxybenzyl) -3,6,9-tris (carboxylatomethyl) -3,6,9-triazaundecanoic acid disodium salt. Gadoxetate disodium has the structure of the following general formula (a) in an aqueous solution.

In order to synthesize the compound of the general formula (a), (S) -N ^1- (2-aminoethyl) -3- (4-ethoxyphenyl) propane-1,2-diamine is an intermediate. 2,2 ′-(2-((2- (bis (carboxymethyl) amino) -3- (4-ethoxyphenyl) propyl) carboxymethyl) amino) ethylazanediyl) diacetic acid is a Chinese patent. It is disclosed in application CN104761461. However, (S) —N ^1- (2-aminoethyl) -3- (4-ethoxyphenyl) propane-1,2-diamine trihydrochloride used as a reactant from the commercially available compound 4-bromophenetole There is no literature which discloses the method of manufacturing.

As intermediates that can be used in the production of gadoxetate disodium, the present inventors have (S) -N ^1- (2-aminoethyl) -3- (4-alkoxyphenyl) propane-1,2-diamine trihydrochloride. Long-term studies have been carried out to find ways to provide salts, and as a result, a series of processes involving Grignard coupling from 1-halo-4-ethoxybenzene has been performed (S) -N ^1- (2-aminoethyl) It was confirmed that this was an economical and simple method enabling efficient mass production of -3- (4-alkoxyphenyl) propane-1,2-diamine trihydrochloride, and the present invention was completed.

To achieve the above object, an exemplary embodiment of the present invention includes (S) -N ^1- (2-aminoethyl) -3- (4-alkoxyphenyl) propane-1,2-, which comprises the following steps: A method for producing diamine trihydrochloride is provided:
(1) A step of producing a compound of the general formula (2) by Grignard coupling of a compound of the general formula (1); (2) In the reaction with sodium azide, the compound of the general formula (2) is generally substituted by azide substitution. A step of producing a compound of formula (3); (3) a step of producing an aziridine derivative of general formula (4) having an amino group protected by cyclization of the compound of general formula (3) with triphenylphosphine. (4) a step of producing a compound of the general formula (5) by opening the compound of the general formula (4); and (5) a reaction for removing the amino protecting group of the compound of the general formula (5) Preparing the compound of general formula (6) by:
Wherein X is bromo or chloro,
R is C _1-6 alkyl. ).

  For example, X may be bromo.

  For example, R may be ethyl.

Conventionally, a method for producing (S) —N ^1- (2-aminoethyl) -3- (4-alkoxyphenyl) propane-1,2-diamine trihydrochloride uses a compound containing a hydroxyl group, further alkoxy, For example, it was carried out by including a step of introducing ethoxy, and there was a disadvantage that further hydrogenation was required using Pd / C to remove unnecessary functional groups. Thus, the present invention is commercially available and using (S) -N ^1- (2-aminoethyl) -3 with a simple compound that is readily available with minimal such unnecessary processes. It is technically characterized to streamline the process for producing-(4-alkoxyphenyl) propane-1,2-diamine trihydrochloride.

Specifically, step (1) can be performed by Grignard coupling. For example, in step (1), a step (1-1) of producing a Grignard compound by reacting a compound of the general formula (1) with a metal or an organometallic compound; and a compound of the general formula (7) and a Grignard compound It can be carried out by reacting step (1-2):

  The metal or organometallic compound in step (1-1) may be any substance known in the art that can be produced as a Grignard compound, but is not limited thereto. For example, the compound may be magnesium, but is not limited thereto.

  The solvent in step (1) is not limited and may be any organic solvent generally used for Grignard coupling. For example, the solvent may be tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, or a mixture thereof, specifically tetrahydrofuran (THF), but is not limited thereto.

  Specifically, the step (1-1) may be performed at a temperature of 20 ° C. to 60 ° C. Step (1-1) is a step of producing a Grignard compound by reacting a halogen compound and a metal. If the step is performed at a high temperature, an undesirable side reaction may be caused. Therefore, after slowly adding the reactants at a low temperature of 20 ° C. to 30 ° C., the temperature may be increased for the reaction, but the method of adjusting the temperature is not limited thereto.

  Further, the step (1-2) may be performed at a temperature of -20 ° C to 30 ° C, specifically 0 ° C to 20 ° C, but is not limited thereto. The reactant used in (1-2) has high reactivity, and therefore it is desirable to perform the reaction at a low temperature. For example, adding the reactant at a low temperature of −5 ° C. can prevent the reaction in an undesirable direction.

Step (1-2) may be performed by further including a Lewis acid as a catalyst. Specific examples of the Lewis acid include CuBrS (CH ₃ ) ₂ , CuI, and CuCl _2. Specifically, CuI may be used, but is not limited thereto.

  Step (1) may be further followed by at least one step of isolating, purifying, and concentrating the produced compound, but is not limited thereto. For example, according to an exemplary embodiment, the prepared compound of step (1) is extracted using an organic solvent, and the resulting organic layer is washed using an aqueous EDTA solution and a 20% aqueous sodium chloride solution. Followed by drying over sodium sulfate and filtration. The filtrate was concentrated to obtain the produced compound.

  In the production method of the present invention, step (2) may be carried out by substituting the chloro group of the halogen-containing compound obtained in step (1), such as chloro, with an azide.

  The solvent of step (2) is not limited and may be any organic solvent commonly used in azide substitution. For example, the solvent may be dimethylformamide, but is not limited thereto.

  Meanwhile, step (2) may be performed at a temperature of 70 ° C. to 100 ° C., for example, 80 ° C. to 90 ° C. or 80 ° C. to 85 ° C., but is not limited thereto.

  After step (2), at least one step of isolating, purifying, and concentrating the prepared compound may be further performed, but is not limited thereto. For example, according to an exemplary embodiment, the compound produced in step (2) is extracted using an organic solvent, and the resulting organic layer is extracted with aqueous hydrochloric acid, 5% aqueous sodium bicarbonate, and 10% chloride. Wash with aqueous sodium followed by drying over sodium sulfate and filtering. The filtrate was concentrated to obtain the produced compound.

  Specifically, the step (3) includes the step (3-1) of forming an aziridinyl group of the general formula (3-1) by cyclization with triphenylphosphine; and the aziridinyl group obtained in the step (3-1). Can be carried out by the step (3-2) of introducing a protecting group into an amino group by reacting a compound containing bis and di-tert-butyl dicarbonate.

In the formula, R is the same as defined above.

  For example, R may be ethyl.

  That is, after the hydroxy group and the azide group of the compound of the general formula (3) are condensed to form an aziridinyl group that is a ring structure containing an amino group, a tert-butyl protecting group is introduced into the amino group of the aziridinyl group. Also good.

Step (3-2) is a catalyst such as 4-dimethylaminopyridine and iodine (I ₂ ) or an alkaline substance such as triethanolamide (TEA), N, N-diisopropylethylamine (DIEA), and NaHCO _3. However, the present invention is not limited to this.

  For example, step (3) may be performed using acetonitrile, toluene, or a mixture thereof as a solvent. Specifically, the solvent may be acetonitrile, but is not limited thereto.

  In addition, the step (3-1) may be performed at a temperature of 55 ° C. to 70 ° C., specifically 60 ° C. to 65 ° C., but is not limited thereto.

  The step (3-2) may be performed at a temperature of 20 ° C. to 30 ° C., specifically, 20 ° C. to 25 ° C., but is not limited thereto.

  Ring opening in step (4) may be performed using acetonitrile, tetrahydrofuran, toluene, or a mixture thereof as a solvent. Specifically, the solvent may be acetonitrile, but is not limited thereto.

  Further, step (4) may be performed at a temperature of 45 ° C. to 55 ° C., specifically, 50 ° C. to 52 ° C., but is not limited thereto.

  On the other hand, the step (5) of removing the amino protecting group may be performed using trifluoroacetic acid, hydrochloric acid, methanolic hydrochloric acid, or a mixture thereof. Specifically, methanolic hydrochloric acid may be used, but is not limited thereto.

  Step (5) may be performed using methanol, dichloromethane, tetrahydrofuran, or a mixture thereof, specifically methanol, as a solvent.

  Meanwhile, in step (5), the methanolic hydrochloric acid may be provided by mixing acetyl chloride with a methanol solvent, but is not limited thereto.

  Further, step (5) may be performed at a temperature of 45 ° C. to 55 ° C., specifically 50 ° C. to 52 ° C., but is not limited thereto.

  Further, after steps (4) and (5) are completed independently, steps (4) and (5) are used to crystallize the produced compound in the respective steps (4-1) or ( Either or both of the steps of 5-1) may be further included.

  For example, step (4-1) may be performed using ethanol, ethyl acetate, or a mixture thereof as a solvent. Specifically, the compound of the general formula (5) may be crystallized using a mixture of ethanol and ethyl acetate as a solvent, but is not limited thereto.

  Meanwhile, step (5-1) may be performed using methanol, acetone, methyl tert-butyl ether, or a mixture thereof as a solvent. Specifically, the compound of the general formula (6) may be crystallized using methyl tert-butyl ether as a solvent, but is not limited thereto.

The production method of the present invention uses (S) -N ^1- (2-aminoethyl) -3- (4-alkoxyphenyl) propane-1,2- by using a reasonably priced raw material and a simple reaction process. It enables efficient and economical production of diamine trihydrochloride and can be usefully applied to its commercial mass production.

  Hereinafter, the present invention will be described in detail with reference to the accompanying drawings. However, the exemplary embodiments disclosed herein are for illustrative purposes only and should not be construed as limiting the scope of the invention.

Hereinafter, samples and solvents without specific disclosure were purchased from Sigma-Aldrich Korea, and ¹ H-NMR spectroscopy was performed using a Bruker 400 MHz NMR spectrometer.

  Examples 1 to 5 were performed according to the following reaction formula.

Example 1: Preparation of (R) -1-chloro-3- (4-ethoxyphenyl) propan-2-ol In a reactor purged with nitrogen atmosphere, magnesium (14.50 g, 596.84 mmol) was added to 600 mL. In addition to THF, the mixture was stirred to dissolve. 4-Bromophenetole (120.0 g, 596.84 mmol) was slowly added while maintaining the temperature at 20-30 ° C. After the addition was complete, the temperature was raised to 60 ° C. and the mixture was stirred for 2 hours and then cooled to −5 ° C., followed by addition of copper iodide (0.76 g, 2.98 mmol) and the mixture was stirred for an additional 30 minutes. . (R) -epichlorohydrin (49.70 g, 537.15 mmol) was then added slowly and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the temperature was lowered to 5 ° C., and aqueous hydrochloric acid (3M, 600 mL) and isopropyl ether (360 mL) were added to separate the layers. The organic layer was washed twice with 10% aqueous EDTA solution (480 mL) and 20% aqueous sodium chloride solution (240 mL), dried over sodium sulfate, and the mixture was filtered. The filtrate was concentrated to obtain the title compound (R) -1-chloro-3- (4-ethoxyphenyl) propan-2-ol (123.2 g, yield 100%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ (ppm) 1.41 (t, 3H), 2.17 (d, 1H), 2.83 (d, 2H), 3.49 to 3.61 ( m, 2H), 4.00 to 4.04 (m, 3H), 6.85 (d, 2H), 7.14 (d, 2H).

Example 2: Production of (R) -1-azido-3- (4-ethoxyphenyl) propan-2-ol (R) -1-chloro-3- (4-ethoxyphenyl) propane produced in Example 1 2-ol (115.33 g, 537.15 mmol) was added to 580 mL of dimethylformamide and the mixture was stirred to dissolve. Then sodium iodide (8.05 g, 53.72 mmol) and sodium azide (69.85 g, 107.39 mmol) were added thereto. The temperature in the reactor was raised to 85 ° C. and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, and purified water (580 mL) and isopropyl ether (580 mL) were added to separate the layers. Thereafter, the obtained aqueous layer was further extracted twice with isopropyl ether (190 mL). The collected organic layer was washed with aqueous hydrochloric acid solution (1M, 580 mL), 5% aqueous sodium hydrogen carbonate solution (580 mL), and 10% aqueous sodium chloride solution (580 mL), dried over sodium sulfate, and the mixture was filtered. The filtrate was concentrated to obtain the title compound (R) -1-azido-3- (4-ethoxyphenyl) propan-2-ol (113.5 g, yield 95.5%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ (ppm) 1.41 (t, 3H), 1.97 (d, 1H), 2.71-2.79 (m, 2H), 3.28 ( dd, 1H), 3.38 (dd, 1H), 3.94-4.01 (m, 1H), 4.04 (q, 2H), 6.86 (d, 2H), 7.10 (d 2H).

Example 3: Preparation of (S) -tert-butyl 2- (4-ethoxybenzyl) aziridine-1-carboxylate (R) -1-Azide prepared in Example 2 in a reactor purged with nitrogen atmosphere -3- (4-Ethoxyphenyl) propan-2-ol (113.0 g, 510.71 mmol) was added to acetonitrile (AN, 1130 mL) and the mixture was stirred, followed by triphenylphosphine (PPh ₃ , 120.56 g). 459.64 mmol) was added and stirred at room temperature for 2 hours and refluxed for 4 hours. After completion of the reaction, the mixture was cooled to 20 ° C. and 4-dimethylaminopyridine (DMAP, 0.62 g, 122.17 mmol) and di-tert-butyl dicarbonate ((Boc) ₂ O, 100.32 g, 458.64 mmol). ) Was added slowly and the mixture was stirred for 30 minutes. Hydrogen peroxide (11.60 g, 102.14 mmol) was added to the mixture and stirred for an additional 30 minutes before the product was concentrated to remove acetonitrile. Heptane (1130 mL) was added to the resulting concentrate and stirred at 20 ° C. to 25 ° C. for 30 minutes, and then the product was filtered. The filtrate was concentrated to obtain the title compound (S) -tert-butyl 2- (4-ethoxybenzyl) aziridine-1-carboxylate (113.05 g, yield 93.9%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ (ppm) 1.39-1.45 (m, 12H), 2.01 (d, 1H), 2.29 (d, 1H), 2.57- 2.62 (m, 2H), 2.91 (q, 1H), 4.02 (q, 2H), 6.84 (d, 2H), 7.20 (d, 2H).

Example 4: Preparation of (S) -tert-butyl 1- (2-aminoethylamino) -3- (4-ethoxyphenyl) propan-2-ylcarbamate dihydrochloride (S)-prepared in Example 3 tert-Butyl 2- (4-ethoxybenzyl) aziridine-1-carboxylate (133.05 g, 479.70 mmol) was added to acetonitrile (400 mL) and the mixture was stirred to dissolve, followed by ethylenediamine (432.45 g , 7195.52 mmol), and the mixture was stirred at 50 ° C. for 6 hours. After completion of the reaction, the product was concentrated, the internal temperature was lowered to 5 ° C., aqueous hydrochloric acid (2M, 480 mL) and ethyl acetate (266 mL) were added and the layers were separated. To the aqueous layer was added 50% aqueous sodium hydroxide solution (200 mL), and the mixture was separated with ethyl acetate (530 mL). The organic layer was washed with 20% sodium chloride (266 mL), dried over sodium sulfate and the mixture was filtered. The filtrate was dried in vacuo at 50 ° C. and the title compound (S) -tert-butyl 1- (2-aminoethylamino) -3- (4-ethoxyphenyl) propan-2-ylcarbamate dihydrochloride (135 0.5 g, yield 68.8%).

¹ H-NMR (D ₂ O, 400 MHz): δ (ppm) 1.02 (s, 2H), 1.14 (s, 9H), 1.24 (t, 3H), 2.46 (dd, 1H ), 2.82 (dd, 1H), 3.07 (t, 1H), 3.25-3.39 (m, 6H), 3.94-4.00 (m, 3H), 6.83 ( d, 2H), 7.10 (d, 2H).

Example 5: Preparation of (S) -N ^1- (2-aminoethyl) -3- (4-ethoxyphenyl) propane-1,2-diamine trihydrochloride A reactor was charged with methanol (950 mL) and acetyl chloride ( 77.75 g, 990.55 mmol) was added and the mixture was stirred to dissolve. To this solution was added (S) -tert-butyl 1- (2-aminoethylamino) -3- (4-ethoxyphenyl) propan-2-ylcarbamate dihydrochloride (135.5 g, 330) prepared in Example 4. .18 mmol) was added and the mixture was stirred at 50 ° C. for 1 h. After completion of the reaction, methyl tert-butyl ether (950 mL) was added, and the mixture was crystallized and filtered. The obtained crystals were vacuum-dried at 50 ° C. and the title compound (S) —N ^1- (2-aminoethyl) -3- (4-ethoxyphenyl) propane-1,2-diamine trihydrochloride (105 .2 g, yield 99.8%).

¹ H-NMR (D ₂ O, 400 MHz): δ (ppm) 1.38 (t, 3H), 3.00 (dd, 1H), 3.17 (dd, 1H), 3.43 to 3.58 (M, 6H), 3.94 to 4.01 (m, 1H), 4.13 (q, 2H), 7.03 (d, 2H), 7.31 (d, 2H).

Claims (21)

A process for producing (S) -N ^1- (2-aminoethyl) -3- (4-alkoxyphenyl) propane-1,2-diamine trihydrochloride comprising the following steps:
(1) producing a compound of general formula (2) by Grignard coupling of the compound of general formula (1);
(2) a step of producing a compound of the general formula (3) by azide substitution of the compound of the general formula (2) in the reaction with sodium azide;
(3) A step of producing an aziridine derivative of the general formula (4) having an amino group protected by an amino protecting group by cyclization of the compound of the general formula (3) with triphenylphosphine;
(4) producing a compound of general formula (5) by ring-opening the compound of general formula (4); and (5) by a reaction to remove the amino protecting group of the compound of general formula (5). Step for producing a compound of the general formula (6):
(Wherein X is bromo or chloro and R is C _1-6 alkyl). Stage (1) includes the following stages:
(1-1) reacting a compound of general formula (1) with a metal or organometallic compound to produce a Grignard compound; and (1-2) reacting the Grignard compound with a compound of general formula (7). Stage to make:
The method of claim 1 comprising: The method of claim 1, wherein step (1) is performed using tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, or a mixture thereof as a solvent.   The method according to claim 2, wherein step (1-1) is performed at a temperature of 20C to 60C.   The method according to claim 2, wherein step (1-2) is performed at a temperature of -20 ° C to 30 ° C.   The method according to claim 2, wherein step (1-2) is performed by further comprising a Lewis acid.   The process according to claim 1, wherein step (2) is carried out using dimethylformamide as a solvent.   The method according to claim 1, wherein step (2) is performed at a temperature of 70C to 100C. Stage (3) is the following stage:
(3-1) a step of forming an aziridinyl group of the general formula (3-1) by cyclization with triphenylphosphine; and (3-2) a compound containing an aziridinyl group obtained by the step (3-1) and di- introducing a protecting group into the amino group by reacting with tert-butyl dicarbonate:
(Wherein R is the same as defined in claim 1).
The method of claim 1 comprising: Step (3-2) is selected from a catalyst selected from 4-dimethylaminopyridine and iodine (I ₂ ), or triethanolamide (TEA), N, N-diisopropylethylamine (DIEA), and NaHCO ₃ The method according to claim 9, wherein the method is performed by further comprising an alkaline substance.   The process according to claim 1, wherein step (3) is carried out using acetonitrile, toluene or a mixture thereof as a solvent.   The method according to claim 9, wherein the step (3-1) is performed at a temperature of 55C to 70C.   The method according to claim 9, wherein step (3-2) is performed at a temperature of 20C to 30C.   The process according to claim 1, wherein step (4) is carried out using acetonitrile, tetrahydrofuran, toluene or mixtures thereof as a solvent.   The process according to claim 1, wherein step (4) is carried out at a temperature between 45C and 55C.   The process according to claim 1, wherein the reaction of step (5) is carried out with trifluoroacetic acid, hydrochloric acid, methanolic hydrochloric acid, or mixtures thereof.   The method of claim 1, wherein step (5) is performed using methanol, dichloromethane, tetrahydrofuran, or a mixture thereof as a solvent.   The process according to claim 1, wherein the reaction of step (5) is carried out with acetyl chloride in a methanol solvent.   The process according to claim 1, wherein step (5) is carried out at a temperature between 45C and 55C.   Step (4) and Step (5) further comprise either or both of the respective steps (4-1) or (5-1) for independently crystallizing the prepared compound. The method of claim 1. Step (4-1) is performed using ethanol, ethyl acetate, or a mixture thereof as a solvent, and Step (5-1) is performed using methanol, acetone, methyl tert-butyl ether, or a mixture thereof as a solvent. 21. The method of claim 20, wherein the method is carried out using.